Acne vulgaris, or simply, acne, is a skin disease affecting 80% of the human population from 11 to 30 years of age; and, as such, is the most common skin disease in the United States. If not properly treated acne may continue into middle age, resulting in permanent scarring, disfigurement, as well as emotional problems. Although treatment options exist, effective treatment is becoming more difficult due to the emergence of systemic antibiotic-resistant strains of Propionibacterium acnes, the bacteria responsible for acne.
Resistance to traditional anti-acne antibiotics is reported to have risen from “extremely rare” in the mid-1980's to over 60% in 1996. It is now estimated that 1 in 4 acne patients are infected by acne strains resistant to at least one of the major systemic antibiotics traditionally used by dermatologists. Cooper, Med. J. Aust., 169:259-261 (1998).
Rosacea is a chronic dermatitis of the face, especially of the nose and cheeks, characterized by a red or rosy coloration caused by dilation of capillaries, and the appearance of acne-like pimples. This condition is also called “acne rosacea,” and is caused by similar bacterial agents in the skin. Rosacea has similarly become more resistant to traditional antibiotic therapies in recent years.
Conventional topical therapies for acne, depending on the severity and extent of the disease, include treatment of the patient with one or more of the following therapeutic agents: (1) comedolytic agents, such as salicylic acid, tretinoin, adapalene, azelaic acid, and tazarotene; (2) bactericidal agents, such as benzoyl peroxide; (3) topical antibiotics, such as clindamycin, erythromycin and tetracycline; and (4) antimicrobial agents, such as sodium sulfacetamide and metronidazole, which can act as anti-inflammatories.
Topically applied benzoyl peroxide (“BP”) is considered the drug agent of choice in the effort to eliminate resistant acne strains. BP is clinically superior to the antibiotics in its ability to kill acne bacteria while continuing to repress resistant strains. In addition, BP is highly lipophilic and concentrates itself inside the lipid-rich, sebaceous, skin follicles where its bacterial action specifically targets P. acnes; and, despite its continued use, it does not cause resistant strains to develop. In fact, BP was found to be more effective than either clindamycin or erythromycin in killing the bacteria responsible for causing acne. Leyden, Cutis, 67 (suppl. 2):5-7 (2001); Leyden et al., Am. J. Clin. Derm., 2(1):33-39 (2001).
While topical medicaments containing BP have been used for at least several decades as a treatment for acne and rosacea, the formulations containing BP have generally been restricted to creams, gels and high viscosity liquids or lotions wherein BP can be suspended either in a colloidal matrix or a slurry. Liquid BP formulations proposed in the art, e.g., in U.S. Pat. No. 6,740,330, contain substantial concentrations of solvents highly irritating and/or drying to the skin, e.g., acetone. Dermatologically safe, truly solubilized BP formulations have not been available in the prior art. Such liquid formulations are desirable to allow BP to be applied to the affected skin sites by, e.g., a dab-on sponge or foam-tipped applicator associated with a reservoir, both for convenience and comfort of use and to allow greater penetration of BP into the skin layers than is achieved with conventional creams and gels. With greater penetration, lower concentrations of BP can be used.
The problem in creating liquid BP formulations is that BP is virtually insoluble in water and most solvents that may be safely used in dermatological preparations and do not cause undue irritation. BP is most soluble in solvents which are unsuitable for application to the skin in substantial concentrations, e.g., acetone, ethers, benzene or chloroform, or in solvents wherein the BP is unstable and degrades rapidly, e.g., propylene glycol formulations of which also have an undesirable greasy feel. In fact it has been found that BP stability in hydric solvents bears an inverse relationship to its solubility, with the least stable formulations being those using hydric vehicles wherein BP is most soluble. Chellquist et al., Pharm. Res., 9:1341-1346 (1992). Indeed, Chellquist et al. recommend using suspension formulations of BP in vehicles that exhibit low BP solubility in order to decrease BP degradation and achieve stability.
Since BP is not soluble in many dermatologically safe vehicles, it must be micropulverized in order to reduce particle size even when the BP is formulated as a suspension in a gel or cream vehicle; otherwise, the user can feel the gritty texture of the BP when the cream or gel is applied to the skin. Furthermore, formulating BP in creams, gels or lotions sometimes requires heating of various phases after the BP is added. Such pulverization or shearing of dry BP particles or heating of BP in suspension is quite dangerous because BP is very unstable and potentially explosive when heated or stressed (and milling processes generate substantial heat as well). Many accidental explosions have been reported worldwide in the production, storage and handling of BP bulk material. As a result, BP raw material is typically supplied and packaged phlegmatized (desensitized) with water to make it safe to transport and use.
It has been found that relatively stable submicron emulsions of BP can be formulated using surfactant/co-surfactant/oil/water mixtures, e.g., ternary mixtures of Cremophor EL, glycerin, caprylic-capric triglycerides and water. Nielloud et al., Drug Devel. Ind. Pharm., 28:863-870 (2002). Such microemulsions, however, are viscous, and despite the submicron size of the BP particles, they still tend to deposit in and clog the pores or cells of a sponge or foam-tip applicator, eventually preventing the exit of the BP-containing emulsion from the reservoir.
Topical liquid medicaments containing true, stable solutions of BP in pharmaceutically effective concentrations are required.